Cardiac hypertrphy is the most important contributor to cardiovascular morbidity and mortality in western[unreadable] societies. Caridac hypertrophy develops in order to maintain cardiac function against an increasing[unreadable] workload. Early in the process, this hypertrophic response may be beneficial but sustained hypertrophic[unreadable] activation ultimately leads to myocardial dysfunction. Interestingly, the intracellular pathways controlling the[unreadable] development of hypertrophy and which mediate the progression from hypertrophy to heart failure are[unreadable] unclear. Timely activation of humoral factors, such angiotensin II (ANG II) and insulin-like-growth factor-1[unreadable] (IGF-1), delineate the activation processes of specific protein kinases whose integrated responses leads to[unreadable] the early beneficial cardiac hypertrophy and later to heart failure. IGF-1 administration can induce[unreadable] hypertrophy as well as block cardiac apoptosis; however ANG II can activate both processes. In the heart,[unreadable] activation of phophatidylinositol (PI) 3-kinase is critical to the ability of IGF-1 to block apoptosis. In contrast,[unreadable] the Ras/MAP (mitogen-activated protein) kinase pathway, which can be activated by both IGF-1 and ANG II,[unreadable] has been associated with cardiac hypertrophy. We have found that compensated eccentric cardiac[unreadable] hypertrophy is associated with enhanced activation of these kinases; whereby alterations in potassium and[unreadable] calcium ion channels induced by ANG II and IGF-1 are mainly mediated through MAP kinase and PI 3-[unreadable] kinase activation. The goals of this porposal is to understand the biological roles of specific downstream[unreadable] signaling pathways in controlling cardiocyte apoptosis and hypertrophy, and to delineate the contribution of[unreadable] apoptosis to the development of heart failure. This porposal is based on 3 hypotheses: 1) signaling[unreadable] pathways responsible for the ability of IGF-1 to induce hypertrophy and block apoptosis are distinct; 2)[unreadable] activation of PI 3-kinase accounts for the benefial effects of IGF-1 on cardiocyte survival; and 3) apoptosis[unreadable] contributes to the development of cardiac dysfunctin in heart failure. To test these hypotheses, we will use[unreadable] adenoviral vectors to express wild-type and mutant-forms of specific signaling molecules in cardiocytes. The[unreadable] long term goal is understanding the role of specific signaling pathways in cardiocyte apoptosis and[unreadable] developing approaches to local modulation of these pathways through somatic gene transfer; which may[unreadable] provide novel therapeutic appraoches for the management of many clinically important disorders.